Gamma-secretase inhibitors (GSIs), which block the presenilin-gamma secretase complex, inhibit the production of amyloidogenic A peptides involved in the pathogenesis of Alzheimer's disease and the activation of NOTCH receptors. Recent identification of activating mutations in the NOTCH1 receptor gene in over 50% of cases of T-cell lymphoblastic leukemia (T-ALL) prompted the initiation of a clinical trial to test the effectiveness of blocking NOTCH1 signaling with a small molecule GSI in this disease. However, the clinical development of GSI-based therapies has been hampered by the limited ability of these drugs to induce apoptosis in human T-ALL and by the development of severe gastrointestinal toxicity due to inhibition of NOTCH signaling in the gut. Over the last two years our group has used a combination of ChIP-on-chip analysis and microarray gene expression profiling to elucidate the structure of the transcriptional regulatory network controlled by oncogenic NOTCH1 signaling in T-ALL. This research has revealed fundamental aspects of the oncogenic program activated by NOTCH1. In this Competitive Revision Application we will expand the scope of our project to the elucidation of genes and pathways controlled by NOTCH signaling in intestinal epithelial cells. These studies will provide valuable information regarding the mechanisms mediating the development of gastrointestinal toxicity upon systemic inhibition of NOTCH signaling with GSIs. PUBLIC HEALTH RELEVANCE: Gamma-secretase inhibitors (GSIs), which block the presenilin-gamma secretase complex, are promising drugs for the treatment of human cancer. However, the clinical development of GSI-based therapies has been hampered the development of severe gastrointestinal toxicity due to inhibition of NOTCH signaling in the gut. This Competitive Revision Application address the mechanisms mediating the development of gastrointestinal toxicity upon systemic inhibition of NOTCH signaling with GSIs.